INTRODUCTION
Thyroid disease is the second most common endocrine disease to affect pregnancy.[1-3] Pregnancy may lead to initiation or aggravation pathophysiological changes of thyroid hormone affecting the feto-maternal thyroid hormone balance.[3,4] Changes of thyroid hormone status during pregnancy are part of normal physiology. However, the detecting pathological changes from the physiological changes often proves to be difficult during pregnancy as those changes are influenced by multiple factors-gestational age, ethnicity, investigation methods, geographical position, and nutritional status of the population. Hence, it is a necessity to establish individualized thyroid hormone reference intervals for the different populations across the world for better management of thyroid related complications during pregnancy. Since there are no such reference intervals in Bangladesh yet, the aim of this study was to address the physiological change of thyroid status during pregnancy for Bangladeshi people and establish trimester-specific reference intervals for thyroid hormone.
MATERIALS AND METHODS
Following the approval of the institutional ethical committee this cross-sectional study was conducted at Antenatal Clinic of a Medical College in Dhaka, Bangladesh. Minimum sample size was calculated considering 95% confidence level, 5% margin of errors and 50% population proportion (did not take any reference from other population and in Bangladesh there was no such study). 1937 cases were randomly selected. After taking informed written consent, all cases were subjected to screening through history taking, physical examination, and laboratory investigations. All women with uncomplicated singleton pregnancy consuming iodized salt and thyroid-stimulating hormone (TSH) level within normal (nonpregnant) laboratory reference value (0.35–5.5 mIU/mL) were eligible for the study. Participants having present or history of thyroid disorder (TD), any chronic or acute illness which may alter thyroid function, large goiter, recent history of consuming thyroid status influencing medications (e.g., steroid, amiodarone, and lithium), family history of TDs, presence of thyroid antibodies-thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb) were not considered for the study. Gestational age was calculated from the 1st day of the last normal menstrual period and gestational age ≤12, 13–28, and >28 weeks comprised the 1st, 2nd, and 3rd trimesters of pregnancy, respectively.
The serum concentration of total thyroxine (TT4) and total triiodothyronine (TT3) increase during pregnancy as serum thyroxine-binding globulin (TBG) concentration increases under the influence of estrogen. The concentration of TBG doubles by 16th–20th weeks of gestation which causes slight decline of free triiodothyronine (FT3) and free thyroxine (FT4) levels in the second and third trimester. Moreover, free thyroid hormone immunoassays are also affected by increased TBG. Hence, it is technically easier and accurate to measure total thyroid hormones than free thyroid hormones during later part of gestation.[2,4,5] A surge of beta-human chorionic gonadotropin (b-HCG) level between 7th and 11th weeks of gestation causes a reduction in serum TSH concentration which usually returns to normal by 18th week.[3] After that the thyroid hormone status usually does not have any significant change. For better understanding of the thyroid hormonal change of Bangladeshi pregnant women, we have also divided the gestational period into 4 stages – ≤7, 8–18, 19–28, and >28 weeks.
Serum TSH concentrations usually provide the first clinical indicator for thyroid dysfunction. A small change in thyroxine concentration causes significant change in serum TSH.[5] Considering all these factors we have decided TSH as our primary investigation tool to monitor patient’s thyroid status unless situation warranted other investigations – FT3/TT3, FT4/TT4, b-HCG. Thyroid antibodies – TPOAb and TgAb were measured for all cases. Hormones and thyroid antibodies were analyzed by using electrochemiluminescence (ECL) immunoassay with IMMULITE 1000 (Siemens, Germany) immunoassay analyzer. Statistical analysis – mean ± standard deviation (SD), percentiles, independent sample t-test were done using SPSS version 23 (IBM, New York, USA) software. For descriptive statistics; percentiles and mean with SDs of different variables were calculated. t-test was used to compare the means of two independent sets of samples. The P values were two-tailed and the probability of significant difference was considered at the level of <0.05.
RESULTS
A total of 1937 cases were enrolled for the study. After initial screening total of 458 cases were excluded as 169 of them were diagnosed cases for TD, 165 cases had a positive family history of TD, 106 had goiter, 17 had acute illness and 1 was on steroid. Among the rest of the cases, 187 cases were found to have subchorionic hemorrhage (SCH), 79 had hyperthyroidism, 32 had overt hypothyroidism and 143 were TPOAb positive. They too were not considered for the study.
The remaining 1038 cases were found eligible for the study. 263 of them reported in 1st trimester, 522 in 2nd trimester and 253 in 3rd trimester. The mean age of the study population was 28.06 ± 4.633 ranging from 18 years to 42 years. The mean gestational ages of the study population while checking thyroid function during 1st, 2nd, and 3rd trimesters were 8.83 ± 2.344 weeks, 19.99 ± 4.824 weeks and 31.77 ± 2.123 weeks respectively. Gestational changes in thyroid status were assessed by calculating the mean ± SD, 2.5th, 50th, 95th, 97.5th percentiles of serum TSH concentration of the study population during different periods of gestation [Table 1].
;)
Table 1: Change of thyroid-stimulating hormone level during gestation
DISCUSSION
Several studies across the globe have been conducted on the assessment of thyroid function test (TFT) among pregnant women. Yet it is difficult to establish a universal reference value of TFTs due to heterogeneity in ethnicity, study design, selection criteria, laboratory methods and other factors. Endocrine society (ES) reported trimester-specific cut-off values for TSH as 0.1–2.5 mIU/L, 0.2–3 mIU/L, and 0.3–3 mIU/L in 1st, 2nd, and 3rd trimesters, respectively.[2] On the other hand, the American Thyroid Association (ATA) suggested to consider TSH level ≥4 mIU/L as abnormal if trimester specific cutoff values for the specific population are not available.[3]
According to ES guidelines, among the selected cases of this study 183 cases would be diagnosed with SCH-63 in 1st trimester, 83 in 2nd trimester, and 37 in 3rd trimester. Whereas, according to ATA the number would be 8, 25, and 5 in 1st, 2nd, and 3rd trimesters, respectively. If we did consider the 97.5th percentile value of TSH of the present study population as reference value then the SCH case number would be 8 in 1st trimester, 15 in 2nd trimester, and 6 in 3rd trimester. The comparison showed that a number of cases would be over-treated if we did follow the ES and ATA recommendation for our study population. Sletner et al. have reported higher TSH level among the south Asian population than the Europeans during gestation.[26] Price et al. have also reported similar results while comparing Asian and western Caucasian pregnant and nonpregnant women.[27]
Many studies [Table 2] on trimester-specific change have reported that TSH level gradually increase as the gestational period progresses or remain unchanged in 2nd and 3rd trimesters TFT.[8-11,15-17,19,21-25] However, in this study, we have observed that TSH level increased significantly (1.85 ± 1.00 vs. 2.03 ± 1.02; P = 0.018) from 1st trimester to 2nd trimester then decreased in 3rd trimester though the decline was not statistically significant (2.03 ± 1.02 vs. 1.90 ± 0.90; P = 0.071). Similar changes of TSH were also reported by few studies.[6,7,18,20] However, when we considered the week-specific changes, there were significant changes throughout the gestational period-decrease of TSH level after 7 weeks of gestation up to 18th weeks (2.19 ± 1.06–1.80 ± 0.97, P = 0.006), then increment until 28th weeks (1.80 ± 0.97–2.14 ± 1.04, P = 0.001) after that again decline of TSH level (2.14 ± 1.04–1.90 ± 0.90, P = 0.005). Earlier Peeters et al. have described the differences in TSH bioactivity due to genetic variability in the gene regulating the TSH receptor.[28] The gestational change of TSH level, we have observed in the present study highlights the importance of individuality of different population. However, this study could not establish the importance of method specific reference intervals, as despite using same laboratory method (ECL technique) the reference intervals of this study were different [Table 2] than the other studies.[7,9,10,14]
Table 2: Trimester-specific change of thyroid-stimulating hormone level in various studies
Despite being a single-center study, we had the opportunity to include a large number of study population residing in different parts of Bangladesh, which reduced the chances of biased results.
One of the important limitations of this study is, we did not analyze the entire thyroid hormone profile (TT3, TT4, FT4, FT3; TSH) of each patient which could create better impression for thyroid hormonal changes during pregnancy. Another limitation is, we did not asses the iodine status of the patients though patients came from regions where iodine reserve in the soil were different. Patient’s confirmation of taking iodinated salt considered as an indicator of good iodine status. We also could not measure arsenic exposure and selenium level of the patients due to our limited resources. As we know that Bangladesh in one of the worst affected countries by arsenic toxicity and the soil of this country is selenium deficient. Both arsenic toxicity and selenium deficiency can alter normal thyroid hormone physiology.[29]
The application of nonpregnant reference intervals to interpret TFTs of pregnant women should not be an ideal approach. TFTs are inconsistent during pregnancy being influenced by pregnancy itself, ethnicity, nutritional status (i.e., iodine and selenium) and test methods. One large-scale study will not be enough to establish a population specific reference interval-more studies are required exploring new variables and new possibilities.
CONCLUSION
The thyroid hormone plays a vital role in pregnancy outcomes and fetal development. Hence, accurate diagnosis is particularly important. In this study, we tried to establish trimester-specific reference value of TFT for Bangladeshi pregnant women. A better understanding of gestational thyroid hormonal change of Bangladeshi women can help physicians to reach the correct diagnosis and take the appropriate management preventing thyroid-related complications during gestation.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. Shahid MM, Ferdousi S. Prevalence and incidence of thyroid disorder during pregnancy in Bangladesh –A tertiary care hospital based study. Sri Lanka J Diabet Endocrinol Metab 2021; 11: 26.
2. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of thyroid dysfunction during pregnancy and postpartum: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2012; 97: 2543–65.
3. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid 2017; 27: 315–89.
4. Soldin OP. Thyroid function testing in pregnancy and thyroid disease:
Trimester-specific reference intervals. Ther Drug Monit 2006; 28: 8–11.
5. Lazarus JH. Thyroid function in pregnancy. Br Med Bull 2011; 97: 137–48.
6. Maji R, Nath S, Lahiri S, Saha Das M, Bhattacharyya AR, Das HN. Establishment of
trimester-specific reference intervals of serum TSH &fT4 in a pregnant Indian population at North Kolkata. Indian J Clin Biochem 2014; 29: 167–73.
7. Marwaha RK, Chopra S, Gopalakrishnan S, Sharma B, Kanwar RS, Sastry A, et al. Establishment of reference range for thyroid hormones in normal pregnant Indian women. BJOG 2008; 115: 602–6.
8. Stricker R, Echenard M, Eberhart R, Chevailler MC, Perez V, Quinn FA, et al. Evaluation of maternal thyroid function during pregnancy: The importance of using gestational age-specific reference intervals. Eur J Endocrinol 2007; 157: 509–14.
9. Moon HW, Chung HJ, Park CM, Hur M, Yun YM. Establishment of
trimester-specific reference intervals for thyroid hormones in Korean pregnant women. Ann Lab Med 2015; 35: 198–204.
10. Rajput R, Singh B, Goel V, Verma A, Seth S, Nanda S.
Trimester-specific reference interval for thyroid hormones during pregnancy at a tertiary care hospital in Haryana, India. Indian J Endocrinol Metab 2016; 20: 810–5.
11. Mehran L, Amouzegar A, Delshad H, Askari S, Hedayati M, Amirshekari G, et al.
Trimester-specific reference ranges for thyroid hormones in Iranian pregnant women. J Thyroid Res 2013 2013. 651517.
12. Cotzias C, Wong SJ, Taylor E, Seed P, Girling J. A study to establish gestation-specific reference intervals for thyroid function tests in normal singleton pregnancy. Eur J Obstet Gynecol Reprod Biol 2008; 137: 61–6.
13. Yan YQ, Dong ZL, Dong L, Wang FR, Yang XM, Jin XY, et al.
Trimester- and method-specific reference intervals for thyroid tests in pregnant Chinese women: Methodology, euthyroid definition and iodine status can influence the setting of reference intervals. Clin Endocrinol (Oxf) 2011; 74: 262–9.
14. Almomin AM, Mansour AA, Sharief M.
Trimester-specific reference intervals of thyroid function testing in pregnant women from Basrah, Iraq Using Electrochemiluminescent Immunoassay. Diseases 2016; 4: 20.
15. Pramanik S, Mukhopadhyay P, Bhattacharjee K, Bhattacharjee R, Mukherjee B, Mondal SA, et al.
Trimester-specific reference intervals for thyroid function parameters in Indian pregnant women during final phase of transition to iodine sufficiency. Indian J Endocrinol Metab 2020; 24: 160–4.
16. Boas M, Forman JL, Juul A, Feldt-Rasmussen U, Skakkebaek NE, Hilsted L, et al. Narrow intra-individual variation of maternal thyroid function in pregnancy based on a longitudinal study on 132 women. Eur J Endocrinol 2009; 161: 903–10.
17. Soldin OP, Tractenberg RE, Hollowell JG, Jonklaas J, Janicic N, Soldin SJ.
Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: Trends and associations across trimesters in iodine sufficiency. Thyroid 2004; 14: 1084–90.
18. Ollero MD, Toni M, Pineda JJ, Martínez JP, Espada M, Anda E. Thyroid function reference values in healthy iodine-sufficient pregnant women and influence of thyroid nodules on thyrotropin and free thyroxine values. Thyroid 2019; 29: 421–9.
19. Wei Q, Zhang L, Liu XX, Pu XM, Xu Y. Clinical analysis of the specific reference intervals of thyroid index for normal pregnant women. Zhonghua Fu Chan Ke Za Zhi 2018; 53: 299–303.
20. Nazarpour S, Ramezani Tehrani F, Simbar M, Minooee S, Rahmati M, Mansournia MA, et al. Establishment of
trimester-specific reference range for thyroid hormones during pregnancy. Clin Biochem 2018; 53: 49–54.
21. Azizi F, Mehran L, Amouzegar A, Delshad H, Tohidi M, Askari S, et al. Establishment of the
trimester-specific reference range for free thyroxine index. Thyroid 2013; 23: 354–9.
22. Panesar NS, Li CY, Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 2001; 38: 329–32.
23. Donovan LE, Metcalfe A, Chin A, Yamamoto JM, Virtanen H, Johnson JA, et al. Apractical approach for the verification and determination of site and
trimester-specific reference intervals for thyroid function tests in pregnancy. Thyroid 2019; 29: 412–20.
24. Huang C, Wu Y, Chen L, Yuan Z, Yang S, Liu C. Establishment of assay method- and
trimester-specific reference intervals for thyroid hormones during pregnancy in Chengdu, China. J Clin Lab Anal 2021; 35: e23763.
25. Akarsu S, Akbiyik F, Karaismailoglu E, Dikmen ZG. Gestation specific reference intervals for thyroid function tests in pregnancy. Clin Chem Lab Med 2016; 54: 1377–83.
26. Sletner L, Jenum AK, Qvigstad E, Hammerstad SS. Thyroid function during pregnancy in a multiethnic population in Norway. J Endocr Soc 2021; 5: bvab078.
27. Price A, Obel O, Cresswell J, Catch I, Rutter S, Barik S, et al. Comparison of thyroid function in pregnant and non-pregnant Asian and western Caucasian women. Clin Chim Acta 2001; 308: 91–8.
28. Peeters RP, van Toor H, Klootwijk W, de Rijke YB, Kuiper GG, Uitterlinden AG, et al. Polymorphisms in thyroid hormone pathway genes are associated with plasma TSH and iodothyronine levels in healthy subjects. J Clin Endocrinol Metab 2003; 88: 2880–8.
29. Shahid M, Begum K, Rahman K, Ara H, Ferdousi S, Gomes R. Thyroid disorders in arsenic prevalent area in Bangladesh. Thyroid Res Pract 2021; 18: 19.
